Color Atlas of Pharmacology (Part 4): Drug Elimination

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Color Atlas of Pharmacology (Part 4): Drug Elimination

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Compared with hydrophilic drugs not undergoing transport, lipophilic drugs are more rapidly taken up from the blood into hepatocytes and more readily gain access to mixed-function oxidases embedded in sER membranes. For instance, a drug having lipophilicity by virtue of an aromatic substituent (phenyl ring) (B) can be hydroxylated and, thus, become more hydrophilic (Phase I reaction, p. 34). Besides oxidases, sER also contains reductases and glucuronyl transferases. The latter conjugate glucuronic acid with hydroxyl, carboxyl, amine, and amide groups (p. 38); hence, also phenolic products of phase I metabolism (Phase II conjugation). Phase I and Phase II...

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  1. 32 Drug Elimination The Liver as an Excretory Organ Compared with hydrophilic drugs not undergoing transport, lipophilic As the chief organ of drug biotransfor- drugs are more rapidly taken up from mation, the liver is richly supplied with the blood into hepatocytes and more blood, of which 1100 mL is received readily gain access to mixed-function each minute from the intestines oxidases embedded in sER membranes. through the portal vein and 350 mL For instance, a drug having lipophilicity through the hepatic artery, comprising by virtue of an aromatic substituent nearly 1/3 of cardiac output. The blood (phenyl ring) (B) can be hydroxylated content of hepatic vessels and sinusoids and, thus, become more hydrophilic amounts to 500 mL. Due to the widen- (Phase I reaction, p. 34). Besides oxi- ing of the portal lumen, intrahepatic dases, sER also contains reductases and blood flow decelerates (A). Moreover, glucuronyl transferases. The latter con- the endothelial lining of hepatic sinu- jugate glucuronic acid with hydroxyl, soids (p. 24) contains pores large carboxyl, amine, and amide groups (p. enough to permit rapid exit of plasma 38); hence, also phenolic products of proteins. Thus, blood and hepatic paren- phase I metabolism (Phase II conjuga- chyma are able to maintain intimate tion). Phase I and Phase II metabolites contact and intensive exchange of sub- can be transported back into the blood stances, which is further facilitated by — probably via a gradient-dependent microvilli covering the hepatocyte sur- carrier — or actively secreted into bile. faces abutting Disse’s spaces. Prolonged exposure to certain sub- The hepatocyte secretes biliary strates, such as phenobarbital, carbama- fluid into the bile canaliculi (dark zepine, rifampicin results in a prolifera- green), tubular intercellular clefts that tion of sER membranes (cf. C and D). are sealed off from the blood spaces by This enzyme induction, a load-depen- tight junctions. Secretory activity in the dent hypertrophy, affects equally all en- hepatocytes results in movement of zymes localized on sER membranes. En- fluid towards the canalicular space (A). zyme induction leads to accelerated The hepatocyte has an abundance of en- biotransformation, not only of the in- zymes carrying out metabolic functions. ducing agent but also of other drugs (a These are localized in part in mitochon- form of drug interaction). With contin- dria, in part on the membranes of the ued exposure, induction develops in a rough (rER) or smooth (sER) endoplas- few days, resulting in an increase in re- mic reticulum. action velocity, maximally 2–3 fold, that Enzymes of the sER play a most im- disappears after removal of the induc- portant role in drug biotransformation. ing agent. At this site, molecular oxygen is used in oxidative reactions. Because these en- zymes can catalyze either hydroxylation or oxidative cleavage of -N-C- or -O-C- bonds, they are referred to as “mixed- function” oxidases or hydroxylases. The essential component of this enzyme system is cytochrome P450, which in its oxidized state binds drug substrates (R- H). The FeIII-P450-RH binary complex is first reduced by NADPH, then forms the ternary complex, O2-FeII-P450-RH, which accepts a second electron and fi- nally disintegrates into FeIII-P450, one equivalent of H2O, and hydroxylated drug (R-OH). Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  2. Drug Elimination 33 Hepatocyte Biliary capillary Disse´s space Intestine Portal vein Gall-bladder A. Flow patterns in portal vein, Disse’s space, and hepatocyte Phase I- metabolite sER rER Biliary capillary C. Normal hepatocyte Phase II- metabolite Glucuronide rER Carrier sER B. Fate of drugs undergoing D. Hepatocyte after B. hepatic hydroxylation D. phenobarbital administration Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  3. 34 Drug Elimination Biotransformation of Drugs mucosa (erythromycin succinate erythromycin). In these cases, the ester Many drugs undergo chemical modifi- itself is not active, but the cleavage cation in the body (biotransformation). product is. Thus, an inactive precursor Most frequently, this process entails a or prodrug is applied, formation of the loss of biological activity and an in- active molecule occurring only after hy- crease in hydrophilicity (water solubil- drolysis in the blood. ity), thereby promoting elimination via Some drugs possessing amide the renal route (p. 40). Since rapid drug bonds, such as prilocaine, and of course, elimination improves accuracy in titrat- peptides, can be hydrolyzed by pepti- ing the therapeutic concentration, drugs dases and inactivated in this manner. are often designed with built-in weak Peptidases are also of pharmacological links. Ester bonds are such links, being interest because they are responsible subject to hydrolysis by the ubiquitous for the formation of highly reactive esterases. Hydrolytic cleavages, along cleavage products (fibrin, p. 146) and with oxidations, reductions, alkylations, potent mediators (angiotensin II, p. 124; and dealkylations, constitute Phase I re- bradykinin, enkephalin, p. 210) from actions of drug metabolism. These reac- biologically inactive peptides. tions subsume all metabolic processes Peptidases exhibit some substrate apt to alter drug molecules chemically selectivity and can be selectively inhib- and take place chiefly in the liver. In ited, as exemplified by the formation of Phase II (synthetic) reactions, conju- angiotensin II, whose actions inter alia gation products of either the drug itself include vasoconstriction. Angiotensin II or its Phase I metabolites are formed, for is formed from angiotensin I by cleavage instance, with glucuronic or sulfuric ac- of the C-terminal dipeptide histidylleu- id (p. 38). cine. Hydrolysis is catalyzed by “angio- The special case of the endogenous tensin-converting enzyme” (ACE). Pep- transmitter acetylcholine illustrates tide analogues such as captopril (p. 124) well the high velocity of ester hydroly- block this enzyme. Angiotensin II is de- sis. Acetylcholine is broken down at its graded by angiotensinase A, which clips sites of release and action by acetylchol- off the N-terminal asparagine residue. inesterase (pp. 100, 102) so rapidly as to The product, angiotensin III, lacks vaso- negate its therapeutic use. Hydrolysis of constrictor activity. other esters catalyzed by various este- rases is slower, though relatively fast in comparison with other biotransforma- tions. The local anesthetic, procaine, is a case in point; it exerts its action at the site of application while being largely devoid of undesirable effects at other lo- cations because it is inactivated by hy- drolysis during absorption from its site of application. Ester hydrolysis does not invariably lead to inactive metabolites, as exempli- fied by acetylsalicylic acid. The cleavage product, salicylic acid, retains phar- macological activity. In certain cases, drugs are administered in the form of esters in order to facilitate absorption (enalapril enalaprilate; testosterone undecanoate testosterone) or to re- duce irritation of the gastrointestinal Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  4. Drug Elimination 35 Esterases Ester Peptidases Amides Anilides Acetylcholine Converting enzyme I sin Acetic acid ten gio II sin An ten III gio sin Choline An ten gio Procaine An Angiotensinase p-Aminobenzoic acid Diethylaminoethanol Acetylsalicylic acid Prilocaine Acetic acid Salicylic acid N-Propylalanine Toluidine A. Examples of chemical reactions in drug biotransformation (hydrolysis) Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  5. 36 Drug Elimination Oxidation reactions can be divided and S-dearylation proceed via an analo- into two kinds: those in which oxygen is gous mechanism (e.g., phenacetin and incorporated into the drug molecule, azathioprine, respectively). and those in which primary oxidation Oxidative deamination basically causes part of the molecule to be lost. resembles the dealkylation of tertiary The former include hydroxylations, amines, beginning with the formation of epoxidations, and sulfoxidations. Hy- a hydroxylamine that then decomposes droxylations may involve alkyl substitu- into ammonia and the corresponding ents (e.g., pentobarbital) or aromatic aldehyde. The latter is partly reduced to ring systems (e.g., propranolol). In both an alcohol and partly oxidized to a car- cases, products are formed that are con- boxylic acid. jugated to an organic acid residue, e.g., Reduction reactions may occur at glucuronic acid, in a subsequent Phase II oxygen or nitrogen atoms. Keto-oxy- reaction. gens are converted into a hydroxyl Hydroxylation may also take place group, as in the reduction of the pro- at nitrogen atoms, resulting in hydroxyl- drugs cortisone and prednisone to the amines (e.g., acetaminophen). Benzene, active glucocorticoids cortisol and pred- polycyclic aromatic compounds (e.g., nisolone, respectively. N-reductions oc- benzopyrene), and unsaturated cyclic cur in azo- or nitro-compounds (e.g., ni- carbohydrates can be converted by trazepam). Nitro groups can be reduced mono-oxygenases to epoxides, highly to amine groups via nitroso and hydrox- reactive electrophiles that are hepato- ylamino intermediates. Likewise, deha- toxic and possibly carcinogenic. logenation is a reductive process involv- The second type of oxidative bio- ing a carbon atom (e.g., halothane, p. transformation comprises dealkyla- 218). tions. In the case of primary or secon- Methylations are catalyzed by a dary amines, dealkylation of an alkyl family of relatively specific methyl- group starts at the carbon adjacent to transferases involving the transfer of the nitrogen; in the case of tertiary methyl groups to hydroxyl groups (O- amines, with hydroxylation of the nitro- methylation as in norepinephrine [nor- gen (e.g., lidocaine). The intermediary adrenaline]) or to amino groups (N- products are labile and break up into the methylation of norepinephrine, hista- dealkylated amine and aldehyde of the mine, or serotonin). alkyl group removed. O-dealkylation In thio compounds, desulfuration results from substitution of sulfur by oxygen (e.g., parathion). This example O2 again illustrates that biotransformation is not always to be equated with bio- R1 inactivation. Thus, paraoxon (E600) formed in the organism from parathion N (E605) is the actual active agent (p. 102). R2 CH3 R1 N OH R2 CH3 Desalkylierung Desalkylierung R1 O + H C N CH3 R2 H L llmann, Color Atlas of Pharmacology ' 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  6. Drug Elimination 37 Propranolol Pentobarbital Hydroxylation Lidocaine Phenacetin Parathion N-Dealkylation Desulfuration O-Dealkylation Norepinephrine Dealkylation S-Dealkylation O-Methylation Azathioprine Methylation Nitrazepam Benzpyrene Chlorpromazine Acetaminophen Sulfoxidation Epoxidation Hydroxyl- amine Reduction Oxidation A. Examples of chemical reactions in drug biotransformation Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  7. 38 Drug Elimination Enterohepatic Cycle (A) Amines may form N-glucuronides that, unlike O-glucuronides, are resistant to After an orally ingested drug has been bacterial !-glucuronidases. absorbed from the gut, it is transported Soluble cytoplasmic sulfotrans- via the portal blood to the liver, where it ferases conjugate activated sulfate (3’- can be conjugated to glucuronic or sul- phosphoadenine-5’-phosphosulfate) furic acid (shown in B for salicylic acid with alcohols and phenols. The conju- and deacetylated bisacodyl, respective- gates are acids, as in the case of glucuro- ly) or to other organic acids. At the pH of nides. In this respect, they differ from body fluids, these acids are predomi- conjugates formed by acetyltransfe- nantly ionized; the negative charge con- rases from activated acetate (acetyl- fers high polarity upon the conjugated coenzyme A) and an alcohol or a phenol. drug molecule and, hence, low mem- Acyltransferases are involved in the brane penetrability. The conjugated conjugation of the amino acids glycine products may pass from hepatocyte into or glutamine with carboxylic acids. In biliary fluid and from there back into these cases, an amide bond is formed the intestine. O-glucuronides can be between the carboxyl groups of the ac- cleaved by bacterial !-glucuronidases in ceptor and the amino group of the do- the colon, enabling the liberated drug nor molecule (e.g., formation of salicyl- molecule to be reabsorbed. The entero- uric acid from salicylic acid and glycine). hepatic cycle acts to trap drugs in the The acidic group of glycine or glutamine body. However, conjugated products remains free. enter not only the bile but also the blood. Glucuronides with a molecular weight (MW) > 300 preferentially pass into the blood, while those with MW > 300 enter the bile to a larger extent. Glucuronides circulating in the blood undergo glomerular filtration in the kid- ney and are excreted in urine because their decreased lipophilicity prevents tubular reabsorption. Drugs that are subject to enterohe- patic cycling are, therefore, excreted slowly. Pertinent examples include digi- toxin and acidic nonsteroidal anti-in- flammatory agents (p. 200). Conjugations (B) The most important of phase II conjuga- tion reactions is glucuronidation. This reaction does not proceed spontaneous- ly, but requires the activated form of glucuronic acid, namely glucuronic acid uridine diphosphate. Microsomal glucu- ronyl transferases link the activated glucuronic acid with an acceptor mole- cule. When the latter is a phenol or alco- hol, an ether glucuronide will be formed. In the case of carboxyl-bearing molecules, an ester glucuronide is the result. All of these are O-glucuronides. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  8. Drug Elimination 39 1 Hepatocyte Sinusoid 4 Biliary capillary Biliary 5 Conjugation with elimination 7 3 glucuronic acid 2 Portal vein E nt er n Deconjugation o h tio epati circula 6 by microbial c !-glucuronidase Renal Lipophilic Enteral 8 elimination drug absorption Hydrophilic conjugation product A. Enterohepatic cycle UDP-"-Glucuronic acid 3'-Phosphoadenine-5'-phosphosulfate Glucuronyl- Sulfo- transferase transferase Salicylic acid Active moiety of bisacodyl B. Conjugation reactions Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  9. 40 Drug Elimination The Kidney as Excretory Organ gree of dissociation. The degree of disso- ciation varies as a function of the uri- Most drugs are eliminated in urine ei- nary pH and the pKa, which represents ther chemically unchanged or as metab- the pH value at which half of the sub- olites. The kidney permits elimination stance exists in protonated (or unproto- because the vascular wall structure in nated) form. This relationship is graphi- the region of the glomerular capillaries cally illustrated (D) with the example of (B) allows unimpeded passage of blood a protonated amine having a pKa of 7.0. solutes having molecular weights (MW) In this case, at urinary pH 7.0, 50 % of the < 5000. Filtration diminishes progres- amine will be present in the protonated, sively as MW increases from 5000 to hydrophilic, membrane-impermeant 70000 and ceases at MW > 70000. With form (blue dots), whereas the other half, few exceptions, therapeutically used representing the uncharged amine drugs and their metabolites have much (orange dots), can leave the tubular lu- smaller molecular weights and can, men in accordance with the resulting therefore, undergo glomerular filtra- concentration gradient. If the pKa of an tion, i.e., pass from blood into primary amine is higher (pKa = 7.5) or lower (pKa urine. Separating the capillary endothe- = 6.5), a correspondingly smaller or lium from the tubular epithelium, the larger proportion of the amine will be basal membrane consists of charged present in the uncharged, reabsorbable glycoproteins and acts as a filtration form. Lowering or raising urinary pH by barrier for high-molecular-weight sub- half a pH unit would result in analogous stances. The relative density of this bar- changes for an amine having a pKa of rier depends on the electrical charge of 7.0. molecules that attempt to permeate it. The same considerations hold for Apart from glomerular filtration acidic molecules, with the important (B), drugs present in blood may pass difference that alkalinization of the into urine by active secretion. Certain urine (increased pH) will promote the cations and anions are secreted by the deprotonization of -COOH groups and epithelium of the proximal tubules into thus impede reabsorption. Intentional the tubular fluid via special, energy- alteration in urinary pH can be used in consuming transport systems. These intoxications with proton-acceptor sub- transport systems have a limited capac- stances in order to hasten elimination of ity. When several substrates are present the toxin (alkalinization phenobarbi- simultaneously, competition for the tal; acidification amphetamine). carrier may occur (see p. 268). During passage down the renal tu- bule, urinary volume shrinks more than 100-fold; accordingly, there is a corre- sponding concentration of filtered drug or drug metabolites (A). The resulting concentration gradient between urine and interstitial fluid is preserved in the case of drugs incapable of permeating the tubular epithelium. However, with lipophilic drugs the concentration gra- dient will favor reabsorption of the fil- tered molecules. In this case, reabsorp- tion is not based on an active process but results instead from passive diffu- sion. Accordingly, for protonated sub- stances, the extent of reabsorption is dependent upon urinary pH or the de- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  10. Drug Elimination 41 Blood Plasma- protein Endothelium Basal membrane Drug 180 L Glomerular Epithelium Primary filtration urine of drug Primary urine B. Glomerular filtration pH = 7.0 pKa of substance pKa = 7.0 100 + 50 Concentration 1.2 L of drug % Final in tubule 6 6.5 7 7.5 8 urine pKa = 7.5 100 A. Filtration and concentration 50 + + + + % + + + 6 6.5 7 7.5 8 + + + + + + + pKa = 6.5 + + + 100 + + + + + Tubular - transport - 50 system for - - - + Cations - - - - - - - - % – - - 6 6.5 7 7.5 8 Anions - - - - - - - pH = 7.0 pH of urine C. Active secretion D. Tubular reabsorption Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  11. 42 Drug Elimination Elimination of Lipophilic and Lipophilic drugs that are convert- Hydrophilic Substances ed in the liver to hydrophilic metab- olites permit better control, because the The terms lipophilic and hydrophilic lipophilic agent can be eliminated in (or hydro- and lipophobic) refer to the this manner. The speed of formation of solubility of substances in media of low hydrophilic metabolite determines the and high polarity, respectively. Blood drug’s length of stay in the body. plasma, interstitial fluid, and cytosol are If hepatic conversion to a polar me- highly polar aqueous media, whereas tabolite is rapid, only a portion of the lipids — at least in the interior of the lip- absorbed drug enters the systemic cir- id bilayer membrane — and fat consti- culation in unchanged form, the re- tute apolar media. Most polar substanc- mainder having undergone presystem- es are readily dissolved in aqueous me- ic (first-pass) elimination. When bio- dia (i.e., are hydrophilic) and lipophilic transformation is rapid, oral adminis- ones in apolar media. A hydrophilic tration of the drug is impossible (e.g., drug, on reaching the bloodstream, glyceryl trinitate, p. 120). Parenteral or, probably after a partial, slow absorption alternatively, sublingual, intranasal, or (not illustrated), passes through the liv- transdermal administration is then re- er unchanged, because it either cannot, quired in order to bypass the liver. Irre- or will only slowly, permeate the lipid spective of the route of administration, barrier of the hepatocyte membrane a portion of administered drug may be and thus will fail to gain access to hepat- taken up into and transiently stored in ic biotransforming enzymes. The un- lung tissue before entering the general changed drug reaches the arterial blood circulation. This also constitutes pre- and the kidneys, where it is filtered. systemic elimination. With hydrophilic drugs, there is little Presystemic elimination refers to binding to plasma proteins (protein the fraction of drug absorbed that is binding increases as a function of li- excluded from the general circulation pophilicity), hence the entire amount by biotransformation or by first-pass present in plasma is available for glo- binding. merular filtration. A hydrophilic drug is Presystemic elimination diminish- not subject to tubular reabsorption and es the bioavailability of a drug after its appears in the urine. Hydrophilic drugs oral administration. Absolute bioavail- undergo rapid elimination. ability = systemically available amount/ If a lipophilic drug, because of its dose administered; relative bioavail- chemical nature, cannot be converted ability = availability of a drug contained into a polar product, despite having ac- in a test preparation with reference to a cess to all cells, including metabolically standard preparation. active liver cells, it is likely to be re- tained in the organism. The portion fil- tered during glomerular passage will be reabsorbed from the tubules. Reabsorp- tion will be nearly complete, because the free concentration of a lipophilic drug in plasma is low (lipophilic sub- stances are usually largely protein- bound). The situation portrayed for a lipophilic non-metabolizable drug would seem undesirable because phar- macotherapeutic measures once initiat- ed would be virtually irreversible (poor control over blood concentration). Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  12. Drug Elimination 43 Hydrophilic drug Lipophilic drug no metabolism Renal Excretion excretion impossible Lipophilic drug Lipophilic drug Slow conversion Rapid and complete in liver to conversion in liver to hydrophilic metabolite hydrophilic metabolite Renal excretion Renal excretion of metabolite of metabolite A. Elimination of hydrophilic and hydrophobic drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
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